Department of Pharmacology, Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon 301 747, South Korea.
Nat Commun. 2013;4:2062. doi: 10.1038/ncomms3062.
Constitutive NF-κB activation in cancer cells is caused by defects in the signalling network responsible for terminating the NF-κB response. Here we report that plant homeodomain finger protein 20 (PHF20) maintains NF-κB in an active state in the nucleus by inhibiting the interaction between PP2A and p65. We show that PHF20 induces canonical NF-κB signalling by increasing the DNA-binding activity of NF-κB subunit p65. In PHF20 overexpressing cells, the termination of tumour necrosis factor-induced p65 phosphorylation is impaired whereas upstream signalling events triggered by tumour necrosis factor are unaffected. This effect strictly depends on the interaction between PHF20 and methylated lysine residues of p65, which hinders recruitment of PP2A to p65, thereby maintaining p65 in a phosphorylated state. We further show that PHF20 levels correlate with p65 phosphorylation levels in human glioma specimens. Our work identifies PHF20 as a novel regulator of NF-κB activation and suggests that elevated expression of PHF20 may drive constitutive NF-κB activation in some cancers.
肿瘤细胞中组成型 NF-κB 的激活是由于负责终止 NF-κB 反应的信号网络缺陷所致。在这里，我们报告植物同源结构域手指蛋白 20（PHF20）通过抑制 PP2A 和 p65 之间的相互作用，将 NF-κB 维持在细胞核中的活跃状态。我们表明 PHF20 通过增加 NF-κB 亚基 p65 的 DNA 结合活性来诱导经典的 NF-κB 信号传导。在 PHF20 过表达的细胞中，肿瘤坏死因子诱导的 p65 磷酸化的终止受到损害，而肿瘤坏死因子触发的上游信号事件不受影响。这种效应严格依赖于 PHF20 与 p65 甲基化赖氨酸残基之间的相互作用，该相互作用阻碍了 PP2A 向 p65 的募集，从而使 p65 保持磷酸化状态。我们进一步表明，PHF20 水平与人脑胶质瘤标本中 p65 磷酸化水平相关。我们的工作确定了 PHF20 作为 NF-κB 激活的新调节剂，并表明 PHF20 的高表达可能在某些癌症中驱动组成型 NF-κB 激活。
